BMC Seminar Wednesday, 21st October at 12:00 in Room 343 in Læknagarður
Speaker: Dr. Hildur H. Arnardóttir, former Postdoctoral Research Fellow at Harvard Medical School & Brigham and Women’s Hospital, Boston, MA, USA. Her overall research focus was on Structure-function relationship of novel bioactive lipid mediators, their pathways and cellular targets in promoting resolution of inflammation. She received her PhD 2011 in Biochemistry and Molecular Biology at University of Iceland, Reykjavik, Iceland in area of Nutritional Immunology. In November she will start as Marie Curie Fellow at the Center for Molecular Medicine, Department of Medicine, Karolinska Institute. Her research focus will be on resolution programs in aortic valvular inflammation and stenosis.
Title: Inflammation-Resolution programs: In aging and human milk
Abstract: A new genus of bioactive mediators, coined specialized proresolving lipid mediators (SPMs) that include the resolvins (Rv), protectins (PD) and maresins (MaR), were recently identified in resolving exudates. These are autacoids biosynthesized from essential fatty acids that actively promote resolution of inflammation. These are structurally distinct families that each display protective roles in experimental models, with defining actions in anti-inflammation (e.g., limit further neutrophil infiltration), pro-resolution (e.g., enhance macrophage clearance of apoptotic cells, debris and bacteria), tissue regeneration and pain reduction and provide a molecular basis for novel therapeutic approaches via promoting resolution. Here, we investigated endogenous resolution programs in aging, in human milk and the roles of SPM.
Aging is associated with chronic, low-grade inflammation leading to progressive physiological decline. Using a self-resolving peritonitis and resolution indices coupled with liquid chromatography tandem masspectrometry (LC-MS-MS)-based lipid mediator (LM) metabololipidomic profiling we uncovered an unappreciated aberrant endogenous resolution program during acute inflammation in aged mice that was associated with deregulation of local SPM levels. These included RvD1, PD1 and MaR1. Increased availability of SPM precursors enhanced endogenous resolution programs in vivo that correlated with increased RvD1 and RvD3. Novel Resolvin-nanoproresolving medicines (NPRM), containing 17R-RvD1 and 17R-RvD3, constructed from reprogrammed monocyte-microparticles reduced the exacerbated inflammatory response in aged mice. Hence, implicating a role for SPM in modulating aged-associated inflammation and rescuing failed resolution in aged mice.
Owing to the immaturity of the immune system in newborns, they have enhanced susceptibility to excessive inflammation and infection. Here we present evidence for new immunoresolving properties of human milk. Using rigorous LC-MS-MS-based LM-SPM metabololipidomics we found that human milk contains chemical signals with pro-resolving actions, namely limiting neutrophil trafficking and microbial phagocytosis in vivo as well as enhancing phagocytosis of apoptotic neutrophils (efferocytosis) and bacterial containment with human macrophages. These actions were attributed to the pro-resolving LM-SPM signature profile of identified bioactive mediators that included D-series resolvins (e.g. 17R-RvD1, RvD2, RvD3, 17R-RvD3 and RvD4), protectins (PD1 and 17R-PD1), maresins (MaR1), E-series resolvins (e.g. RvE2 and RvE3) and lipoxins (e.g. 17R-LXA4 and LXB4). Mastitis human milk gave altered LM-SPM profile with higher eicosanoids (e.g. LTB4, PGF2α, TxB2), lower SPM levels and reduced ability to accelerate resolution. Taken together these findings provide evidence for bioactive resolution signals in human milk that are linked to homeostasis, resolution of inflammation and innate host responses, describing a potentially novel mechanism in maternal-infant biochemical imprinting.